Chronic obstructive pulmonary disease (COPD) is a chronic debilitating disease that afflicts ~24 million Americans and is a major cause of death and disability globally. Research over the past 2 decades has begun to elucidate the critical role of bacterial colonization and infection, particularly by nontypeable Haemophilus influenzae (NTHI), in the course and pathogenesis of COPD. In an 18-year ongoing prospective study, we have established that a large proportion of adults with COPD show persistent airway colonization by NTHI. Although such colonization was previously thought to be innocuous because of the absence of acute symptoms, it is now clear that such colonization contributes to the airway inflammation and impaired pulmonary function that are hallmarks of COPD. The carefully characterized strains from this long-term study allow us to address key areas where opportunities to develop novel interventions in the course of COPD exist.
In aim 1 the evolutionary dynamics of the NTHI genome from serial isolates that lived in the complex environment of the human airways will be elucidated to identify adaptations that facilitate persistence in the airways in COPD.
In aim 2 the effect of immune selective pressure on candidate vaccine antigens will be elucidated. Vaccine development for NTHI is undergoing exciting new developments with the recent licensing of a vaccine that contains an NTHI antigen and preclinical and clinical development of several additional antigens. Monitoring the effect of persistence in the human respiratory tract in driving sequence changes and their consequences on candidate vaccine antigens is critical to assessing such vaccine candidates.
In aim 3 the frequency of antimicrobial resistance markers and tolerance in NTHI that colonize and infect adults with COPD will be studied to assess the effect of antibiotic use in driving resistance mechanisms. The genomes of bacteria harbor antibiotic resistance markers that are undetected by simply measuring antimicrobial susceptibility and thus allow us to anticipate future antibiotic resistance mechanisms. Antibiotic tolerance, a term that refers to persistence in the face of active antibiotic, will be explored as a mechanism of persistence in COPD. It is now clear that chronic bacterial colonization of the airways is a major contributor to airway inflammation and impaired pulmonary function in COPD. The application of state-of-the-art methods to a unique set of strains and detailed associated data make it possible to explore 3 key areas that are unexplored: 1) mechanisms of persistence, 2) the effect of persistence on vaccine antigens and 3) the role of repeated antibiotic exposure in driving antibiotic resistance and tolerance as mechanisms of persistence. Each of these 3 areas is rich in opportunities to develop novel interventions in the course of COPD.

Public Health Relevance

Persistence of nontypeable Haemophilus influenzae in the lower airways of adults with chronic obstructive pulmonary disease (COPD) causes airway inflammation and impaired pulmonary function. This proposal uses state of the art methods to investigate how NTHI persists and the consequences of its persistence. The results will reveal new ways to eradicate persistent NTHI and have great potential for novel discoveries to prolong and improve the lives of people with COPD.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
2R01AI019641-28A1
Application #
8627837
Study Section
Special Emphasis Panel (ZRG1-IDM-V (02))
Program Officer
Taylor, Christopher E,
Project Start
1983-09-30
Project End
2018-08-31
Budget Start
2013-09-20
Budget End
2014-08-31
Support Year
28
Fiscal Year
2013
Total Cost
$455,369
Indirect Cost
$144,624
Name
State University of New York at Buffalo
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
038633251
City
Buffalo
State
NY
Country
United States
Zip Code
14260
Clementi, Cara F; Hakansson, Anders P; Murphy, Timothy F (2014) Internalization and trafficking of nontypeable Haemophilus influenzae in human respiratory epithelial cells and roles of IgA1 proteases for optimal invasion and persistence. Infect Immun 82:433-44
Agrawal, Aarti; Murphy, Timothy F (2011) Haemophilus influenzae infections in the H. influenzae type b conjugate vaccine era. J Clin Microbiol 49:3728-32
Murphy, Timothy F; Brauer, Aimee L (2011) Expression of urease by Haemophilus influenzae during human respiratory tract infection and role in survival in an acid environment. BMC Microbiol 11:183
Nakamura, Shigeki; Shchepetov, Mikhail; Dalia, Ankur B et al. (2011) Molecular basis of increased serum resistance among pulmonary isolates of non-typeable Haemophilus influenzae. PLoS Pathog 7:e1001247
Qu, Jun; Lesse, Alan J; Brauer, Aimee L et al. (2010) Proteomic expression profiling of Haemophilus influenzae grown in pooled human sputum from adults with chronic obstructive pulmonary disease reveal antioxidant and stress responses. BMC Microbiol 10:162
Novotny, Laura A; Adams, Leanne D; Kang, D Richard et al. (2009) Epitope mapping immunodominant regions of the PilA protein of nontypeable Haemophilus influenzae (NTHI) to facilitate the design of two novel chimeric vaccine candidates. Vaccine 28:279-89
Ostberg, K L; Russell, M W; Murphy, T F (2009) Mucosal immunization of mice with recombinant OMP P2 induces antibodies that bind to surface epitopes of multiple strains of nontypeable Haemophilus influenzae. Mucosal Immunol 2:63-73
Cholon, Deborah M; Cutter, David; Richardson, Stephen K et al. (2008) Serial isolates of persistent Haemophilus influenzae in patients with chronic obstructive pulmonary disease express diminishing quantities of the HMW1 and HMW2 adhesins. Infect Immun 76:4463-8
Murphy, Timothy F; Brauer, Aimee L; Sethi, Sanjay et al. (2007) Haemophilus haemolyticus: a human respiratory tract commensal to be distinguished from Haemophilus influenzae. J Infect Dis 195:81-9
Fernaays, Matthew M; Lesse, Alan J; Sethi, Sanjay et al. (2006) Differential genome contents of nontypeable Haemophilus influenzae strains from adults with chronic obstructive pulmonary disease. Infect Immun 74:3366-74

Showing the most recent 10 out of 65 publications